The immunomodulatory receptor CTLA-4 maintains tolerance to self, and Ctla4−/− mice develop lymphoproliferative disorders with tissue infiltration of self-reactive T cells. In Nature Medicine, Kang and colleagues show that signaling via the coreceptor CD28 and the signaling kinase Itk specifically regulates the migration of self-reactive T cell to tissues. The authors show that interactions of CD28 with its ligand B7, between T cells and B7-expressing endothelial cells, modulate the trafficking of Ctla4−/− T cells. Downstream of CD28, Itk is required for the transendothelial migration of Ctla4−/− T cells, although it is not required for the activation of Ctla4−/− T cells or for exit from the lymph nodes. In addition, Itk does not modulate the activity of Ctla4−/− Treg cells. An inhibitor of Itk diminishes the autoimmune tissue infiltration in Ctla4−/− mice and the infiltration and destruction of beta islets in mice of the nonobese diabetic strain, which results in a lower incidence of diabetes.

Nat. Med. (24 November 2013) doi:10.1038/nm.3393